Ischemia and reperfusion-injured liver-derived exosomes elicit acute lung injury through miR-122-5p regulated alveolar macrophage polarization

Abstract

Abstract Background Acute lung injury (ALI) is a common postoperative complication, particularly in pediatric patients after liver transplantation. Exosomes(Exos) are novel regulator of intercellular communications that play important roles in the pathogenesis of ALI. We previously demonstrated that hepatic ischemia-reperfusion (HIR) induces increased release of exosomes (IR-Exo) in the peripheral circulation. Aim We aimed to explore the role of exosomes derived from ischemia-reperfusion-injured liver in the development of ALI. Methods ALI was induced by HIR or IR-Exo, accompanied by the applications of inhibitor of exosomal secretion (GW4869), or miR−122−5p inhibitor in vivo. Lung injury scores, pulmonary edema, inflammatory mediators and macrophage polarization were examined. In vitro, bone marrow-derived macrophages (BMDMs) and alveolar macrophages (AMφ) were induced by IR-Exo or miR−122−5p mimic, along with the applications of miR−122−5p inhibitor. RNA sequencing, dualluciferase reporter assay, qRT-PCR and western blot were performed to clarify the mechanisms of exomal miR−122−5p in ALI. Results We found that intravenous injection of IR-Exo caused lung inflammation in naive rats, while pretreatment with an inhibitor of exosomal secretion (GW4869) attenuated HIR-related lung injury. In vivo and in vitro results show that IR-Exo promoted pro-inflammatory responses and M1 macrophage polarization. Furthermore, miRNA profiling of serum identified miR−122−5p as the highest increased exosomal miRNA of young rats suffering from HIR compared with controls. In addition, IR-Exo transferred miR−122−5p to macrophages and promoted pro-inflammatory responses and M1 phenotype polarization by targeting suppressor of cytokine signaling protein 1 (SOCS−1)/nuclear factor (NF)-κB. Importantly, the pathogenic role of exosomal miR−122−5p in initiating lung inflammation was reversed by inhibition of miR−122−5p. Clinically, higher levels of miR−122−5p were found in serum and correlated with the severity of lung injury in pediatric living-donor liver transplant recipients with ALI. Conclusion Taken together, our findings reveal that IR-Exo transfers liver-specific miR−122−5p to alveolar macrophages and elicits ALI by inducing M1 macrophage polarization via the SOCS−1/NF-κB signaling pathway.